For this K99/R00, I will specifically address the role of anxiety and anatomical sex on Alzheimer?s disease (AD) progression, specifically memory loss. AD, a debilitating neurodegenerative and mental disorder, stands alone as one of the ten leading causes of death in the United States that cannot be prevented, slowed, or cured. Furthermore, neuropsychiatric disturbances, such as depression and anxiety, are observed in 90% of AD patients and are frequent in those at risk for AD. Although most AD studies have been performed using male mice, recent evidence suggests that females are more susceptible to depression, anxiety, and AD when compared to males. In fact, two-thirds of AD patients are women. Here, we aim to identify the neural ensembles linking anxiety and memory loss following AD progression by utilizing behavioral studies, optogenetics, whole-brain microscopy, and in vivo Ca2+ imaging in female and male mice. These studies represent a number of firsts in the AD field: 1) the first to test the controversial hypothesis that anxiety can be a predictor of AD in females; 2) the first to investigate sex differences across the whole brain as the disease progresses; 3) the first to use in vivo Ca2+ imaging to tag an individual memory and asses neuronal activity during behavior in AD mice; and 4) the first to test the therapeutic potential of targeting neural correlates of memory and anxiety in AD mice. In Aim 1, behavioral differences will be correlate anxiety-like behavior with memory loss across numerous ages as AD progresses. In Aim 2, the individual neurons corresponding to a memory will be investigated by utilizing a transgenic line, the ArcCreERT2 mice bred with an AD line (APP/PS1). This mouse line allows for the indelible labeling of cells expressing the immediate early gene (IEG) Arc/Arg3.1 and allows for a comparison between the cells that are activated during the encoding of an experience and those that are activated during the retrieval of the corresponding memory. We will use whole brain imaging to find novel brain regions of interest that are altered during AD. In Aim 3, I will rescue impaired neural networks in AD x ArcCreERT2 mice using optogenetic stimulation in combination with in vivo Ca2+ imaging. The outcome of this targeted rescue will provide direct evidence that disrupted neural ensembles results in the cognitive decline and anxiety-like behavior observed in female AD mice. My overall career goal is to lead an independent research group examining the underlying mechanisms of neurodegeneration and to determine how sex impacts disease progression with the long-term goal of creating personalized therapeutics. This K99/R00 will thus provide me protected time and mentorship to acquire the technical and conceptual skills to successfully achieve my career goals and establish an independent research program geared towards answering clinically driven research questions in the area of neurodegenerative diseases.